The present invention relates to genetic mutations in the promoter and coding regions for the gap junction protein beta 2 (GJB2) associated the recessive DFNB1 locus on chromosome 13, associations of such mutations with non-syndromic hearing impairment (NSHI), and genetic testing in humans for NSHI.
Introduction
Non-syndromic hearing impairment (NSHI) affects almost 1 in 2000 newborn children and is predominantly inherited in an autosomal recessive fashion (Fortnum and Davis, 1997, Epidemiology of permanent childhood hearing impairment in Trent Region, 1985-1993. Br J Audiol 31, 409-446; Morton, 1991, Genetic epidemiology of hearing impairment. Ann N Y Acad Sci 630, 16-31). Within the recessive DFNB1 locus on chromosome 13, alterations in the gap junction proteins beta 2 (GJB2) encoding Connexin 26 (Cx26) and GJB6 (Cx30) are known to cause sensorineural deafness (Denoyelle et al., 1997, Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet 6, 2173-2177; Kelsell et al., 1997, Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387, 80-83). Mutations in GJB2 are the most common associated with up to 50% of NSHI cases (Denoyelle et al., 1997, Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet 6, 2173-2177; Estivill et al., 1998, Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet 351, 394-398) and are routinely assessed in the clinical analysis of genetic hearing impairment. Both targeted ablation and expression of mutant connexins causes hearing loss by impairment of K+ homeostasis within supporting cells during development leading to degradation of the organ of corti (Cohen-Salmon et al., 2002, Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Curr Biol 12, 1106-1111; Kudo et al., 2003, Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness. Hum Mol Genet 12, 995-1004).
The most frequent GJB2 mutation in Caucasian populations is the frameshift deletion of a guanine residue at position 35 of the normal coding sequence (35delG) which leads to the introduction of a premature stop codon after base pairs 37-39 (Zelante et al., 1997, Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet 6, 1605-1609). This mutation has a carrier frequency of 1.7% in Austria for example, where homozygous 35delG is associated with up to 75% of cases of NSHI (Frei et al., 2005, GJB2 mutations in hearing impairment: identification of a broad clinical spectrum for improved genetic counseling. Laryngoscope 115, 461-465).